An epigenetic basis for essential hypertension [thesis]

Matthias Duebbert
Essential hypertension – high blood pressure – is responsible for more disease and deaths worldwide than any other single health risk factor. Despite its thoroughly researched and confirmed heritability, essential hypertension lacks a genetic explanation. An underexplored cause for essential hypertension could be related to epigenetics. Epigenetic states dictate gene expression independent of variation in the underlying DNA sequence, and as such an aberrant epigenetic state would be invisible
more » ... conventional genetic association studies. In this work I proposed to investigate the hypothesis that epigenetic changes could contribute to the development of hypertension. In order to investigate this, I utilised the canonical model for human hypertension, the spontaneously hypertensive rat (SHR). Comparison of cytosine methylation patterns of SHR to the related normotensive Wistar Kyoto rats (WKY) identified thousands of methylation differences between the kidneys of the two strains. Further exploration of the brain and liver of the same animals showed that some of these methylation differences were represented in all three germ layers, and thus hold the potential to be both inborn and transmissible events. Even though the vast majority of differences were located in yet to be annotated regions of the rat genome and could not be explored at this point, at least two candidates for so called "germline epimutations" were identified in Arhgap11a and Tomm20. Neither of the two had previously been linked to hypertension but are involved in biological pathways that can be associated with blood pressure regulation. In a complementary experiment I confirmed that transient exposure to Captopril caused reversion to normotension in the SHR. In contrast to previous reports, lowering of blood pressure was not heritable. However methylation differences induced by transient Captopril treatment were subtle and less numerous than those seen in the comparison of WKY and SHR. Nevertheless, hundreds of methylation differences were found and [...]
doi:10.26190/unsworks/20743 fatcat:vr55n2irdbfbhdigwlhm3isqre